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Citation
Issued Date
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2011
http://hdl.handle.net/10722/173743
By
Declaration
I, Chan Wai Hung, declare that this dissertation represents my own work and
that it has not been submitted to this or other institution in application for a
degree, diploma or any other qualifications.
I, Chan Wai Hung also declare that I have read and understand the guideline on
What is plagiarism? published by The University of Hong Kong (available at
http://www.hku.hk/plagiarism/) and that all parts of this work complies with the
guideline.
Acknowledgement
I have to give my special thanks to Dr. Yau Yat Sun from Department of
Paediatrics, Queen Elizabeth Hospital who actually looks after all the infants
born from HIV infected mothers in last 10 years. Without the work of Dr. Yau,
this piece of work will not be completed and the meaningful clinical information
will not be revealed. Also I need to give thanks to Dr. Chan Lai Har Grace from
Department of Paediatrics and Dr. Li Chung Kee Patrick from Department of
Medicine, Queen Elizabeth Hospital who had pioneered the clinical care of
babies born from HIV infected mothers.
Apart from the medical professionals, the successfulness of the specialist
care provides by the designated hospital relies heavily on the contributions by the
nurse specialist Ms. Yu Pansy, social worker, dietitian, physiotherapist and
occupational therapist. The health and welfare of people living with Human
Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome
(AIDS) and their families depend upon on the hard work by the multidisciplinary
team. Their work is much appreciated.
Abstract
Background:
Mother-To-Child-Transmission
(MTCT)
of
Human
Hence, the MTCT rate is 5.9% in the designated hospital. Serial haemoglobin
(Hb) levels and liver function (LFT) at birth of all infants; lactate only when
infants develop symptoms indicating neurologic involvement are recorded. Only
the Hb levels at birth are moderately lower than normal which indicate mild
transient marrow toxicity.
Conclusions: The MTCT rate in a designated hospital in Hong Kong is
approaching the rate in developed countries after commencement of various
preventive and prophylactic measures for prevention of MTCT in HIV infected
mothers. No significant persistent toxicity of antiretroviral prophylaxis exposure
during antenatal, intrapartum and postnatal period in infants born from HIV
infected mothers is identified. However, prolonged follow up for potential long
term teratogenic and carcinogenic effect is still suggested for such exposure.
(315 words)
Background
The natural MTCT rate of HIV infection in infants is high if there are no
preventive and prophylactic interventions. The MTCT rate in resource poor
countries ranges from 25 to 42% (1). Therefore, various protocols and
methodologies are advocated and actively studied in the last two decades in order
to control further upsurge of such transmission and hopefully abolish all MTCT.
Pediatric AIDS Clinical Trial Group (PACTG) is one of the investigating group
looks into this problem. It set up the PACTG protocol 076 since 1994 and series
of studies were conducted (2-3) and concluded that series of preventive and
prophylactic measures can bring down MTCT rate approximately to 1% to 2%
(4). The most important preventive strategy in unknown HIV status expecting
mothers is universal screening of HIV antibody in all. This measure can screen
out all asymptomatic HIV infected mothers and it is an effective and cost-saving
measure (5-7). For the HIV infected expecting mothers, three aspects of
preventive
measures
are
important
mothers whose HIV RNA viral load more than 1000 copies per ml before
delivery can actually reduce MTCT. Last but not the least, complete avoidance of
breast feeding in resource adequate setting can further help in reducing MTCT as
most of the postnatal acquired infection are from the route of breast milk (8-9).
How about the scenario in Hong Kong? The very first case of HIV
infection was diagnosed in 1984. Since then, there are two designated units
providing specialist care for the people living with HIV and AIDS were set up
since 1980s. One of them is the Special Medical Service of Queen Elizabeth
Hospital (QEH) which provides in-patient as well as out-patient specialist care
for people living with HIV and AIDS. Another unit is the Special Preventive
Programme under the Department of Health provides mainly out-patient
specialist care. It locates in Kowloon Bay Integrated Treatment Centre (KBITC).
The Infectious Disease unit of Princess Margaret Hospital (PMH) joined the
KBITC to provide clinical care of people living with HIV and AIDS since 2001
(10).
Concerning the epidemiology of HIV and AIDS, the incidence was
increasing since 1984 till 1997. The incidence then has a slower rate of increase
probably due to the introduction of HAART in 1997. The incidence was then
gradually increased till 2009 with drops in incidence in two consecutive years.
Up to the first quarter of 2011, the total numbers of HIV and AIDS cases are
4935 and 1198 respectively (22). Hong Kong has low prevalence of HIV
infection and AIDS with prevalence of less than 0.1% in adult population (12-20).
The major route of transmission is sexual contact and the men having sex with
men (MSM) dominate the transmission since 2003 (12-20). MTCT is not the
major route of transmission.
Even though the MTCT is not the major route of transmission in Hong
Kong, the implication of such transmission is huge as every single infant affected
will require long term, probably life long HAART and in the long run, majority
of HIV infection from MTCT will progress into AIDS. The situation before
various preventive and prophylactic measures commenced in Hong Kong is
similar to the rest of the world, i.e. the historical data about MTCT rate. There
are total 14 cases out of 41 HIV infected mothers have MTCT during 1992 to
1999. Therefore, the MTCT rate is 34.1% before all these interventions
commenced (12). In response to the successfulness of various preventive
protocols and strategies to prevent MTCT available, Hong Kong had came up to
a consensus statement of starting universal screening of HIV antibody in all
pregnant women since September 2001 (11). This universal screening test
adopted an opt out mechanism that pregnant mothers have to actively decline
the test in order to have high uptake rate. The strategy was successful that the
coverage rate is high ranging from 96% to 98.2% from September 2001 to 2008
(12-19). However, the coverage rate dropped to 93.8% in 2009 (20), which may
be related to high influx of pregnant women from mainland China in recent few
years that the antenatal visits in Hong Kong may be very late in their pregnancies.
If the trend continues to drop, it may imply that the screening preventive measure
is failing. Six percent opt out rate already means 5280 pregnant women escape
from the screening with the yearly delivery rate of 88,000 in Hong Kong.
After the commencement of universal screening of HIV antibody in all
pregnant women, total 59 pregnant women were screened to be HIV antibody
positive in the period of September 2001 to the end of 2009 (12-20). Hence, the
mean yearly positive HIV antibody screening test is around 7 per year. After
knowing the positive HIV antibody test results, 17 out of the 59 pregnant women
decided not to continue their pregnancies, i.e. overall percentage is 28.8%. It
seems that the initial termination of pregnancies rate is higher in the first 3 years
after commencement of universal HIV antibody screening. Ten out of 24 HIV
infected mothers decided for termination of pregnancies, i.e. 41.6%, during
September 2001 to the end of 2004, while 2 out of 7 decided for termination of
pregnancies, i.e. 28.6%, in 2009. It may be explained by a better education of the
10
Objective
Since the exact MTCT rate in Hong Kong remains uncertain after
commencement of universal HIV antibody screening in all pregnant women, we
conduct a retrospective descriptive study to determine the MTCT rate of HIV
infection in infants born from HIV infected mothers in the designated hospital in
Hong Kong. Therefore, we can compare the MTCT rate before and after
commencement of series of preventive and prophylactic measures in Hong Kong.
We study the potential side effects and toxicities of antiretroviral
prophylaxis exposure to infants, in which antiretroviral prophylaxis is given to
mother during antenatal and intrapartum period, as well as given to infants as
postnatal antiretroviral prophylaxis. Such exposure may post a potential long
term and potential teratogenic and carcinogenic effect on exposed infants.
11
Method
As the Special Medical Service of QEH provides specialist care to people
living with HIV and AIDS since 1980s, significant proportion of newly
diagnosed HIV infected pregnant women will be cared in QEH. Hence, majority
of the HIV infected mothers will have their delivery in QEH. All the HIV
infected mothers are managed according to the recommended clinical guidelines
on prevention of perinatal HIV transmission (21).
Since quite a significant portion of HIV infected mothers choose to have
delivery in QEH, all the infants born from HIV infected mothers will be cared by
Paediatric Infectious Diseases physician from Department of Paediatrics in QEH.
All these newborns are managed according to the clinical pathway on prevention
of MTCT according to the recommended guidelines (2-3,21).
All the newborn infants delivered in Departments of Gynaecology and
Obstetrics (O&G) in all Hospital Authority (HA) hospitals in Hong Kong are
retrieved by Clinical Data Analysis and Reporting System (CDARS) from the
period of 1st January 2002 to 31st December 2010 with the ICD9 diagnostic codes
using Contact with or exposure to HIV - V01.7, or Human immunodeficiency
antibody positive V08, or any history of using postnatal antiretroviral
prophylaxis such as oral (PO) or intravenous (IV) Zidovudine (ZDV), PO
12
13
Results
There are total 54 infants born from HIV infected mothers in O&G
Departments of all HA hospitals of which 17 is from QEH. It accounts for 31.5%
of all infants. Since the current available data from SPP surveillance reports is
only up to 2009, we have shorten the study period from 1st January 2002 to 31st
December 2009 and we still have total 43 infants from all O&G Departments of
all HA hospitals of which 14 is from QEH. It accounts for 32.6% of all infants.
There is discrepancy from data by SPP and data retrieved by CDARS as
there are 5 more infants identified by CDARS. They are probably infants from
mothers who are known to have HIV infection that they are not picked up by the
universal HIV antibody screening.
The exact MTCT rate of infants born from HIV infected mothers in HA
hospitals cannot be arrived because the lack of information on whom has
subsequent HIV infection or not. But from the data available in QEH, there is
only 1 case of infants developed HIV infection despite the adequate preventive
and prophylactic measures. Hence, the MTCT rate of infants born from HIV
infected mothers in QEH is 5.9%.
Demographic data is unremarkable. There are 8 male infants and 9 female
infants. The mean gestation is 37 weeks 4 days. There are 2 premature deliveries.
14
One prematurity delivery was born at 34 weeks 5 days and another at 35 weeks 2
days. All gestations are below 39 weeks as majority of infants were delivered by
earlier elective caesarean sections. The mean birth weight is 2.76 kg with the
range of 1.5 kg to 3.31 kg. Large proportion of infants is from non-Chinese
origin. Eleven out of 17 is non-Chinese which accounts for 64.7%. Various ethnic
groups are involved including Africans, Nepalese, Filipinos, Indonesians and
Thai.
Maternal viral data shows the mean RNA viral load before delivery is 493
copies per ml with the range from undetectable to 1681 copies per ml. The mean
maternal CD4 count before delivery is 465 with the range from less than 200 to
694.
Four out of 17 mothers received HAART for their own health either for
low CD4 count or opportunistic infection such as Pneumocystis jirovercii
infection (PCP) which consists of 23.5% of HIV infected mothers. Two of these
4 mothers are from universal HIV antibody screening and 2 are from women who
are known to have HIV infection. There are 4 mothers are known to have HIV
infection and 2 of them do not need any HAART before this pregnancy.
There are 16 out of 17 caesarean sections, i.e. 94.1% have caesarean
sections to further lower MTCT risk. Only one was delivered vaginally. In this
15
particular case, it was premature delivery and HIV infection was diagnosed
during labour by point of care test (POCT) of HIV antibody. All newborn infants
received formula feeding and none has started breast feeding.
Concerning the potential side effects and toxicities of antiretroviral
prophylaxis exposure in infants, haematologic and biochemical parameters are
collected. The mean Hb level at birth is 16.7 g/dL with the range from 13.5 to
20.9 g/dL. Five out of 17 (29.4%) has neonatal anaemia with Hb level less than
15 g/dL. The mean Hb level at 4 weeks is 11.1 g/dL with the range from 9.5 to
14.4 g/dL. The mean Hb level at 2 months is 11.3 g/dL wit range from 10.5 to
12.5 g/dL. One infant received transfusion of pack cells at 3 weeks of age
because of sepsis that he required IV antibiotics. Haemoglobin level dropped to
10 g/dL and hence, transfusion of pack cells was given once.
Liver function tests at birth are all normal. The mean Alanin Transaminase
(ALT) is 14 IU/L with the range from 8 to 30 IU/L. Only 4 infants had checked
lactate level. One infant developed neonatal seizure after taking 1 week course of
combination antiretroviral prophylaxis (ZDV and 3TC), hence, lactate was
checked. Another 3 infants had checked lactate because of poor feeding and one
had unstable temperature and poor feeding. The mean lactate level is 3.27
mmol/L and the range is from 0.9 to 5.5 mmol/L. Two had high lactate at the first
16
17
Discussion
The MTCT rate of infants born from HIV infected mothers in the
designated hospital in Hong Kong is 5.9%. The MTCT rate is actually
approaching that of the reported best scenario in the literature. It is much better
than the rate before any preventive and prophylactic measures (34.1%) ten to
twenty years ago (12). However, the overall MTCT rate in Hong Kong with
shorter period is still high, up to 20.5% (12-20). It is probably an over estimation
because few cases are reported retrospectively.
In our series, the only infant contracted the HIV infection is mainly
because the mother did not turn up for medical assessment after the HIV
antibody result was known. With repeated efforts, the mother finally returned for
assessment and HAART was only started 1 week before delivery. Then the
intrapartum and postnatal antiretroviral prophylaxis commenced according to the
clinical pathway. However, the infant had high RNA viral load at birth up to 4190
copies per ml. The subsequent RNA viral loads were persistently high and it was
already more than 50,000 copies per ml at 4 months. Hence, confirmatory test by
Western blot at 4 months showed that he has HIV infection. HAART was started
at 6 months of age.
Though we have a significant drop in MTCT rate in our designated
18
19
20
Conclusion
The MTCT rate of HIV infection in infants born from HIV infected
mothers in the designated hospital in Hong Kong is 5.9% after commencement of
universal HIV antibody screening test in all pregnant women. Antiretroviral
prophylaxis exposure to infants causes transient neonatal anaemia but no
significant mitochondrial dysfunction.
Despite the fact that antiretroviral prophylaxis is relatively safe in adults,
we have to look out for long term potential teratogenic and carcinogenic effects
in particular in-utero exposure. We recommend prolonged follow up should be
offered.
The successfulness of preventive and prophylactic measures for prevention
of MTCT in HIV relies on experienced Infectious Disease Physician to look after
mothers HIV infection and offer adequate HAART; experienced Obstetricians to
administer intrapartum antiretroviral prophylaxis and performing elective
caesarean sections; experienced Paediatric Infectious Diseases Physician
administering postnatal antiretroviral prophylaxis, advise on complete avoidance
of breast feeding and managing Paediatric HIV infection; and most importantly
the multidisciplinary team management of patients and families.
21
References
(1) DeCok K, Fowler MG, Mercier E at al. Prevention of mother-to-child
transmission of HIV-1 in resource poor countries: translating research into
policy and practice. JAMA 2000, 283:1175-82
(2) Connor EM, Sperling RS, Gelder RD, et al. Pediatric AIDS Clinical Trials
Group
Protocol
076
Study
Group.
Reduction
of maternal-infant
22
HIV
transmission
in
the
United
States.
Available
at:
Health,
January
2005.
Available
at
http://www.aids.gov.hk/aids/english/publications/pubsearch_1.htm#HIV
23
24
January
2007.
Available
at
http://www.aids.gov.hk/aids/english/publications/pubsearch_1.htm#HIV
Management and Clinical Guidelines
(22) Latest Statistics: Summary table on the HIV/AIDS situation through the
reporting
system
up
to
31
March
2011.
Available
at
http://www.info.gov.hk/aids/english/surveillance/quarter.htm
25
hepatic
enzyme,
hematologic
abnormalities
among
human
of
bone
marrow
cultures.
Toxicological
Sciences.
2000;58(1):96-101
(25) Blanche S, Tardieu M, Rustin P et al. Persistent mitochondrial dysfunction
and
perinatal
exposure
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nucleoside
analogues.
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(26) Poirier MC, Olivero OA, Walker DM et al. Perinatal genotoxicity and
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26
12
10
8
TOP
CS
NSD
6
4
2
0
2005
2006
2007
2008
2009
Table 1: Demographic data of infants and maternal baseline viral load and
CD4 count
Sex
Ethnic group
Gestation
Birth weight
Maternal
viral
Male:Female
8:9
Chinese:Non-Chinese
11:6
Mean
Range
37 wk 4 d
34 wk 5 d 38 wk 4 d
2.76 kg
1.5 3.31 kg
493 cps/ml
UD 1681 cps/ml
27
load
Maternal
CD4
465
count
UD Undetectable, cps/ml copies per ml,
Table 2: Haematologic and liver function parameters of infants
Mean
Range
Hb (g/dL) at birth
16.7
13.5 20.9
Hb (g/dL) at 4 weeks
11.1
9.5 14.4
Hb (g/dL) at 2 months
11.3
10.5 12.5
14
8 - 30
28